Alcohol is implicated as the etiologic agent in greater than 50% of deaths due to liver cirrhosis, a growing national health concern. It is widely accepted that ethanol-induced oxidative injury can result in inflammation, steatohepatitis, hepatocellular carcinoma and fibrosis. However, it is unknown why only a subpopulation of alcoholic liver disease patients present with end stage liver cirrhosis. Likewise, factors contributing to increased obesity-related susceptibility to the deleterious effects of ethanol are poorly understood. This NIAAA R03 has as its primary focus to achieve a basic understanding of whether differences in the severity of alcoholic liver disease can be explained, in part, by alcoholinduced acceleration of preexisting liver injury. This proposal builds on our recent observation that combined hyperlipidemic mice that overexpress apolipoprotein C-I maintained on a chow diet develop prefibrotic liver injury. The hypothesis that will be tested is that alcohol can exacerbate preexisting liver injury initiated by chronic hyperlipidemia. In this study, normolipidemic and hyperlipidemic mice fed alcohol or a control diet will be evaluated for changes in plasma lipids and lipoproteins. Intravital microscopy will be used to monitor liver microcirculation, tissue damage and collagen deposition. Tissue evaluation will indicate the metabolic health and extent of liver injury. This study is of immediate interest because while hyperlipidemia is pandemic in the US, the observation that chronic hyperlipidemia can result in liver injury was previously unappreciated. With our recent observation that chronic hyperlipidemia can result in liver injury we will determine whether alcohol can accelerate the development of liver disease in a spontaneous liver injury model where the damage is initiated by preexisting hyperlipidemia.